Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin

Patti, Gary J.; Yanes, Óscar; Shriver, Leah P.; Courade, Jean-Philippe; Tautenhahn, Ralf; Manchester, Marianne; Siuzdak, Gary

doi:10.1038/nchembio.767

Cited by 173 publications

(176 citation statements)

References 24 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…Exogenous application of neutral sphingomyelinase or C 2 -ceramide increases TTX-resistant sodium currents in the soma of primary sensory neurons (54). In the spinal dorsal horn, neutral sphingomyelinase and ceramide levels are increased in neuropathic rats induced by nerve injury (16). Suppression of ceramide production in the spinal dorsal horn ameliorates neuro- pathic pain, which is accompanied by decreased microglial activation in the spinal dorsal horn (17).…”

Section: Role Of Ceramide In Pathologicalmentioning

confidence: 99%

See 1 more Smart Citation

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Yan

严

Weng

et al. 2013

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

Background: Excessive activation of glutamate receptors is crucial to the genesis of neuropathic pain. Results: Endogenous IL-1␤ in neuropathic rats enhances glutamate release by increasing presynaptic NMDA receptor activities via sphingomyelinase signaling. Conclusion: Coupling between IL-1␤ receptors and presynaptic NMDA receptors contributes to the genesis of neuropathic pain. Significance: Interruption of such coupling could be an effective approach for the treatment of neuropathic pain.

show abstract

Section: Role Of Ceramide In Pathologicalmentioning

confidence: 99%

“…Previous studies showed that levels of ceramide in the spinal dorsal horn are increased in neuropathic animals following nerve injury (16,17) or in morphine-tolerant rats (18). Ceramide is a potent proinflammatory sphingolipid that is generated by hydrolysis of sphingomyelin on the membrane by acid or neutral sphingomyelinase (19).…”

mentioning

confidence: 99%

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Yan

严

Weng

et al. 2013

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

show abstract

“…Thus, to discover novel plasma metabolite biomarkers for VTE risk, we performed liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics in a pilot study to analyze plasma metabolites without any specific targeting of known metabolites (supplemental Figure 1A, available on the Blood Web site). [2][3][4][5][6] One lipid metabolite family, namely, acylcarnitines (ACs), exhibited association with VTE. When AC lipids were tested in coagulation assays for any potential causality relationship, the novel anticoagulant activity of ACs was discovered and was shown to involve targeting of factor Xa.…”

Section: Introductionmentioning

confidence: 99%

Acylcarnitines are anticoagulants that inhibit factor Xa and are reduced in venous thrombosis, based on metabolomics data

Deguchi¹,

Banerjee²,

Trauger

et al. 2015

Blood

Self Cite

View full text Add to dashboard Cite

• Untargeted and targeted metabolomics showed association of low plasma acylcarnitines levels with venous thrombosis risk.• Long-chain acylcarnitines are anticoagulants that inhibit factor Xa by binding to factor Xa outside the g-carboxy glutamic acid domain.In many patients with deep vein thrombosis and pulmonary embolism (venous thromboembolism, VTE), biomarkers or genetic risk factors have not been identified. To discover novel plasma metabolites associated with VTE risk, we employed liquid chromatography-mass spectrometry-based untargeted metabolomics, which do not target any specific metabolites. Using the Scripps Venous Thrombosis Registry population for a case-control study, we discovered that 10:1 and 16:1 acylcarnitines were low in plasmas of the VTE patient group compared with matched controls, respectively. Data from targeted metabolomics studies showed that several long-chain acylcarnitines (10:1, 12:0, 12:2, 18:1, and 18:2) were lower in the VTE group. Clotting assays were used to evaluate a causal relationship for low acylcarnitines in patients with VTE. Various acylcarnitines inhibited factor Xa-initiated clotting. Inhibition of factor Xa by acylcarnitines was greater for longer acyl chains. Mechanistic studies showed that 16:0 acylcarnitine had anticoagulant activity in the absence of factor Va or phospholipids. Surface plasmon resonance investigations revealed that 16:0 acylcarnitine was bound to factor Xa and that binding did not require the g-carboxy glutamic acid domain. In summary, our study identified low plasma levels of acylcarnitines in patients with VTE and showed that acylcarnitines have anticoagulant activity related to an ability to bind and inhibit factor Xa. (Blood. 2015;126(13):1595-1600

show abstract

“…Metabolomics is a relatively recent discipline dedicated to the global study of endogenous metabolites in tissues and biofluids [10][11][12]. Considerable evidence on the identification of the link between endogenous metabolites and symptoms has been obtained from studies using non-targeted metabolomics in the dorsal horn of rats with neuropathic pain [13]. A non-targeted metabolomic approach may be useful to identify EF-induced biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Non-targeted human plasma metabolomics reveals the changes in oleoylethanolamide, a lipid-derived signaling molecule, by acute exposure of electric field

Y¹

2014

Integr Mol Med

View full text Add to dashboard Cite

Medical treatment using high-voltage electric potential (HELP) device to generate an electric field (EF) is an alternative therapy commonly used in Japan. However, little is known about the underlying mechanisms of the potential benefits to health. The identification of EF exposure -related biomarkers is key to understanding the beneficial effects of EF therapy. We screened plasma metabolites obtained prior to and immediately after HELP exposure (18 kV, 30 min) in 10 healthy human subjects by via non-targeted plasma metabolomic analysis. Among 161 metabolites, several fatty acid amides containing a signaling molecule oleoylethanolamide (OEA) and fatty acids were significantly upregulated. Under these conditions, HELP exposure had no effect on citric acid and ornithine cycle intermediates. Because OEA is known to induce lipolysis as a putative endogenous ligand of peroxisome proliferator-activated receptor (PPAR)-α, we further confirmed the effect of OEA on gene expression using human subcutaneous cultured adipocytes. Peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) mRNA was upregulated by OEA treatment. OEA-induced ACOX1 mRNA expression was sensitive to a PPAR-α antagonist GW6471. Our findings will provide the new insights into the molecular mechanisms of EF therapy.

show abstract

Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin

Cited by 173 publications

References 24 publications

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Acylcarnitines are anticoagulants that inhibit factor Xa and are reduced in venous thrombosis, based on metabolomics data

Non-targeted human plasma metabolomics reveals the changes in oleoylethanolamide, a lipid-derived signaling molecule, by acute exposure of electric field

Contact Info

Product

Resources

About